Project abstract Obesity is now an epidemic and has become one of the most common causes of insulin resistance. Insulin resistance is the key etiology for the pathogenesis of metabolic syndrome. Prolonged status of metabolic syndrome drives the development of type 2 diabetes mellitus. An important event in this process is the recruitment and activation of macrophages to the insulin target tissues. However, the mechanisms whereby macrophages regulate the development of obesity-induced insulin resistance are not fully understood. Obesity drives the activation of adipose tissue macrophages (ATM) towards proinflammatory phenotype, which subsequently affects the interaction of macrophages with adipocytes or other insulin target cells. Here, we aim to discover exosomal miRNA-mediated mechanisms underlying the pathogenesis of systemic insulin sensitivity. My preliminary data show that the distinct activations of ATMs signal a switch in profile of exosomal miRNAs that can be delivered into the insulin target cells and exert profound regulation on insulin responses of these cells. In vivo results indicate that transferring obese ATM-secreted exosomes impair glucose tolerance and insulin sensitivity of lean WT recipient mice, while lean ATM exosomes remarkably attenuate insulin resistance of obese WT recipient mice. Therefore, I propose that adipose tissue macrophages secrete exosomal miRNAs as paracrine/endocrine molecules controlling cellular insulin responses of target cells, which eventually mediate systemic insulin sensitivity. To testify this hypothesis, I will 1) investigate the regulation of ATM-derived exosomal miRNAs on cellular insulin actions; 2) investigate the importance of exosomal miR-155 in regulating the insulin responses; 3) determine the mechanisms by which ATM-exosomal miRNAs regulate the cellular insulin responses. This research will elucidate ATM-secreted exosomal miRNA-mediated mechanisms controlling insulin sensitivity, with the ultimate goal of identifying novel targets for therapeutic treatment of insulin resistance and type 2 diabetes.